Abstract
IL-37 is a recently discovered cytokine in the IL-1 family exerting broad protective effects on inflammatory diseases, autoimmune diseases, and cancer. Immune and non-immune cells produce the IL-37 precursor upon pro-inflammatory stimuli. Intracellularly, caspase-1 cleaves and activates IL-37, and its mature form binds to Smad3; this complex translocates into the nucleus where it suppresses cytokine production, consequently reducing inflammation. Extracellularly, IL-37 forms a complex with IL-18Rα and IL-1R8 (formerly TIR8 or SIGIRR) that transduces anti-inflammatory signals by the suppression of NF-κB and MAPK and the activation of Mer-PTEN-DOK pathways. During inflammation, IL-37 suppresses the expression of several pro-inflammatory cytokine in favor to the expression of the anti-inflammatory ones by the regulation of macrophage polarization, lipid metabolism, inflammasome function, TSLP synthesis and miRNAs function. Moreover, IL-37 not only regulates the innate and acquired immunity, but also improves aging-associated immunosenescence. Furthermore, IL-37 exerts an inhibitory effect on tumor angiogenesis and metastasis, and progression. Finally, IL-37 may have a potential ability to reduce excessive inflammation since it is aberrantly expressed in patients with inflammatory diseases, autoimmune diseases, and cancer, thus, it may be used as a marker for different types of diseases. Therefore, this review provides an updated view of the role of IL-37 in human health and disease, and discusses the potential of IL-37 as a therapeutic target and biomarker in inflammatory diseases, autoimmune diseases, and cancer.
Highlights
Human IL-37 is a newly discovered member of the IL-1 family has the ability to inhibit inflammation and immune response by inhibiting the production of pro-inflammatory cytokines, and ameliorate inflammation-induced fatigue by inducing metabolic reprogramming and limiting the metabolic effects of inflammation (1)
IL-37 is a dual function cytokine with both intracellular and extracellular forms that exerts broad and complex antiinflammatory and immunomodulatory effects, inhibits the excess of inflammation, and prevent tissue damage mediated by inflammation
The potential use of IL-37 as a novel therapeutic target may be beneficial in the modulation of the inflammatory, metabolic and immune response as well as cancer development
Summary
Human IL-37 is a newly discovered member of the IL-1 family has the ability to inhibit inflammation and immune response by inhibiting the production of pro-inflammatory cytokines, and ameliorate inflammation-induced fatigue by inducing metabolic reprogramming and limiting the metabolic effects of inflammation (1). Knockdown of IL-37 significantly increased the LPS-induced inflammatory gene and protein expressions in WISH cells, which were reversed by administering recombinant human IL-37 (rhIL-37) (37). IL-37b down-regulates the expression of the TLR3 co-receptor Mex[3] RNA binding family member B (Mex3B) in human nasal epithelial cells (HNECs) in vitro by the inhibition of polyinosinic-polycytidylic acid-induced production of thymic stromal lymphopoietin (TSLP); this effect is observed in vivo in murine nasal epithelial cells (52).
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